The Experts below are selected from a list of 9678 Experts worldwide ranked by ideXlab platform

Yoshiki Kudo - One of the best experts on this subject based on the ideXlab platform.

  • Indoleamine 2 3 dioxygenase distribution and function in the developing human placenta
    Journal of Reproductive Immunology, 2004
    Co-Authors: Osamu Takikawa, Yoshiki Kudo, C A R Boyd, Isabella Spyropoulou, C W G Redman, Takafumi Katsuki, Tetsuaki Hara, Koso Ohama, I L Sargent
    Abstract:

    Abstract Studies in mice have suggested that the placenta is protected from immune rejection by maternal T cells by means of localised Indoleamine 2,3-dioxygenase dependent depletion of tryptophan. To determine whether such mechanisms might operate in the human placenta, we have studied the physiological importance of human placental Indoleamine 2,3-dioxygenase immunohistochemically and functionally. Indoleamine 2,3-dioxygenase is detectable immunohistochemically from day 6 human blastocysts and thereafter throughout pregnancy in syncytiotrophoblasts, extravillous cytotrophoblasts and macrophages in the villous stroma and in the fetal membranes. Interferon-γ added to villous explants markedly stimulates Indoleamine 2,3-dioxygenase protein expression in macrophages. Indoleamine 2,3-dioxygenase-mediated tryptophan degradation in the first trimester villous and decidual tissue explants is stimulated by interferon-γ and inhibited by 1-methyl-tryptophan (an inhibitor of Indoleamine 2,3-dioxygenase). Peripheral blood mononuclear cell proliferation is controlled by Indoleamine 2,3-dioxygenase-mediated tryptophan degradation. These results suggest the cellular basis of a mechanism present at the human maternal–fetal interface involved in regulating the maternal immune response to conceptus.

  • decreased tryptophan catabolism by placental Indoleamine 2 3 dioxygenase in preeclampsia
    American Journal of Obstetrics and Gynecology, 2003
    Co-Authors: Yoshiki Kudo, C A R Boyd, I L Sargent, C W G Redman
    Abstract:

    Abstract Objective: Tryptophan degradation and depletion resulting from activation of Indoleamine 2,3-dioxygenase is characteristic of inflammatory reactions and may control their intensity. Normal third-trimester pregnancy is characterized by a maternal systemic inflammatory response, which is more intense in preeclampsia. Therefore, we studied tryptophan metabolism in pregnant women, with or without preeclampsia, as well as expression and function of placental Indoleamine 2,3-dioxygenase. Study Design: Plasma concentrations of tryptophan and kynurenine in women with preeclampsia, appropriately matched women with normal pregnancy, and healthy nonpregnant women were measured. Placental enzymatic activity and messenger RNA (mRNA) expression level of Indoleamine 2,3-dioxygenase were determined from the same placental material. Peripheral blood mononuclear cell proliferation was determined in medium conditioned by prior culture with villous tissue. Results: The plasma ratio of kynurenine to tryptophan, an in vivo index of enzyme activity, was significantly increased compared with nonpregnant controls in normal pregnancy but not in preeclampsia. The activity and mRNA expression level of Indoleamine 2,3-dioxygenase in term placentas were significantly lower in preeclampsia. Medium conditioned by culture of villous tissue explants of preeclampsia was less effective in inhibiting peripheral blood mononuclear cell proliferation compared with that of normal pregnancy. Conclusion: These observations suggest that in preeclampsia, reduced placental Indoleamine 2,3-dioxygenase activity (and relatively elevated plasma tryptophan) could cause dysregulation of the inflammatory response that is intrinsic to normal pregnancy. This may contribute to the pathogenesis of the maternal syndrome of preeclampsia. (Am J Obstet Gynecol 2003;188:719-26.)

  • tryptophan degradation by human placental Indoleamine 2 3 dioxygenase regulates lymphocyte proliferation
    The Journal of Physiology, 2001
    Co-Authors: Yoshiki Kudo, C A R Boyd, I L Sargent, C W G Redman
    Abstract:

    1. The physiological importance of human placental Indoleamine 2,3-dioxygenase (EC 1.13.11.42), the first and rate-limiting enzyme in tryptophan metabolism, in regulating feto-maternal immunology has been studied. 2. Concentrations were measured in placental villous explant conditioned media of 14 amino acids that are known to be required for lymphocyte proliferation. In the absence of interferon-gamma only tryptophan and threonine were significantly lowered; in the presence of interferon-gamma (known to stimulate Indoleamine 2,3-dioxygenase) tryptophan but not threonine depletion was much greater. 3. Peripheral blood mononuclear cell proliferation determined by measuring thymidine incorporation into DNA following culture in the medium previously conditioned by culture of villous explants was markedly reduced when placental Indoleamine 2,3-dioxygenase was stimulated with interferon-gamma. Inhibition of placental Indoleamine 2,3-dioxygenase by 1-methyl-tryptophan prevented inhibition of thymidine incorporation. Supplementation of the conditioned medium with tryptophan but no other amino acid completely reversed the inhibition of thymidine incorporation. 4. Flow cytometric analysis showed that CD4-positive T lymphocyte division was specifically suppressed by Indoleamine 2,3-dioxygenase-mediated tryptophan depletion. This inhibition of T cell proliferation was due to arrest of cell cycle progression. 5. To study the mechanism of tryptophan sensing we examined the ability of 11 L-tryptophan analogues to support lymphocyte proliferation. Only L-tryptophan methyl and ethyl esters were able to stimulate proliferation in tryptophan-free media. Since both of these molecules are readily degraded to tryptophan by intracellular esterases this suggests that the tryptophan sensor is intracellular. 6. Our results show that mechanisms are present in the human placenta which are able to regulate cellular proliferation of the maternal immune system. This mechanism is dependent both on placental Indoleamine 2,3-dioxygenase-mediated tryptophan degradation and on tryptophan sensing systems within lymphocytes.

  • human placental Indoleamine 2 3 dioxygenase cellular localization and characterization of an enzyme preventing fetal rejection
    Biochimica et Biophysica Acta, 2000
    Co-Authors: Yoshiki Kudo, C A R Boyd
    Abstract:

    Abstract In order to test the hypothesis (Munn, Zhou, Attwood, Bondarev, Conway, Marshall, Brown, Mellor, Science 281 (1998) 1191–1193) that localized placental tryptophan catabolism prevents immune rejection of the mammalian fetus, the cellular localization and characteristics of human placental Indoleamine 2,3-dioxygenase (EC 1.13.11.42) were studied. The localization of Indoleamine 2,3-dioxygenase activity was determined quantitatively using cell fractionation by differential and discontinuous sucrose gradient centrifugation. Enzyme activity was looked for in isolated brush border microvillous plasma membranes of placental syncytiotrophoblast. We found that this membrane preparation (which showed a 32.4-fold purification from the starting homogenate with reference to the activity of a membrane marker enzyme, alkaline phosphatase (EC 3.1.3.1)) was strongly negatively enriched with Indoleamine 2,3-dioxygenase (which showed a one twenty-fifth decrease in its specific activity). Placental Indoleamine 2,3-dioxygenase is thus not expressed in the maternal facing brush border membrane of syncytiotrophoblast. 1-Methyl- dl -tryptophan which was used by Munn et al. as a key experimental tool for inhibiting Indoleamine 2,3-dioxygenase in the murine model showed a competitive inhibition of human placental Indoleamine 2,3-dioxygenase with l -tryptophan. The hypothesis, based on experiments performed in mouse, may therefore be applicable to avoidance of immune rejection of the fetus in human pregnancy.

C A R Boyd - One of the best experts on this subject based on the ideXlab platform.

  • Indoleamine 2 3 dioxygenase distribution and function in the developing human placenta
    Journal of Reproductive Immunology, 2004
    Co-Authors: Osamu Takikawa, Yoshiki Kudo, C A R Boyd, Isabella Spyropoulou, C W G Redman, Takafumi Katsuki, Tetsuaki Hara, Koso Ohama, I L Sargent
    Abstract:

    Abstract Studies in mice have suggested that the placenta is protected from immune rejection by maternal T cells by means of localised Indoleamine 2,3-dioxygenase dependent depletion of tryptophan. To determine whether such mechanisms might operate in the human placenta, we have studied the physiological importance of human placental Indoleamine 2,3-dioxygenase immunohistochemically and functionally. Indoleamine 2,3-dioxygenase is detectable immunohistochemically from day 6 human blastocysts and thereafter throughout pregnancy in syncytiotrophoblasts, extravillous cytotrophoblasts and macrophages in the villous stroma and in the fetal membranes. Interferon-γ added to villous explants markedly stimulates Indoleamine 2,3-dioxygenase protein expression in macrophages. Indoleamine 2,3-dioxygenase-mediated tryptophan degradation in the first trimester villous and decidual tissue explants is stimulated by interferon-γ and inhibited by 1-methyl-tryptophan (an inhibitor of Indoleamine 2,3-dioxygenase). Peripheral blood mononuclear cell proliferation is controlled by Indoleamine 2,3-dioxygenase-mediated tryptophan degradation. These results suggest the cellular basis of a mechanism present at the human maternal–fetal interface involved in regulating the maternal immune response to conceptus.

  • decreased tryptophan catabolism by placental Indoleamine 2 3 dioxygenase in preeclampsia
    American Journal of Obstetrics and Gynecology, 2003
    Co-Authors: Yoshiki Kudo, C A R Boyd, I L Sargent, C W G Redman
    Abstract:

    Abstract Objective: Tryptophan degradation and depletion resulting from activation of Indoleamine 2,3-dioxygenase is characteristic of inflammatory reactions and may control their intensity. Normal third-trimester pregnancy is characterized by a maternal systemic inflammatory response, which is more intense in preeclampsia. Therefore, we studied tryptophan metabolism in pregnant women, with or without preeclampsia, as well as expression and function of placental Indoleamine 2,3-dioxygenase. Study Design: Plasma concentrations of tryptophan and kynurenine in women with preeclampsia, appropriately matched women with normal pregnancy, and healthy nonpregnant women were measured. Placental enzymatic activity and messenger RNA (mRNA) expression level of Indoleamine 2,3-dioxygenase were determined from the same placental material. Peripheral blood mononuclear cell proliferation was determined in medium conditioned by prior culture with villous tissue. Results: The plasma ratio of kynurenine to tryptophan, an in vivo index of enzyme activity, was significantly increased compared with nonpregnant controls in normal pregnancy but not in preeclampsia. The activity and mRNA expression level of Indoleamine 2,3-dioxygenase in term placentas were significantly lower in preeclampsia. Medium conditioned by culture of villous tissue explants of preeclampsia was less effective in inhibiting peripheral blood mononuclear cell proliferation compared with that of normal pregnancy. Conclusion: These observations suggest that in preeclampsia, reduced placental Indoleamine 2,3-dioxygenase activity (and relatively elevated plasma tryptophan) could cause dysregulation of the inflammatory response that is intrinsic to normal pregnancy. This may contribute to the pathogenesis of the maternal syndrome of preeclampsia. (Am J Obstet Gynecol 2003;188:719-26.)

  • tryptophan degradation by human placental Indoleamine 2 3 dioxygenase regulates lymphocyte proliferation
    The Journal of Physiology, 2001
    Co-Authors: Yoshiki Kudo, C A R Boyd, I L Sargent, C W G Redman
    Abstract:

    1. The physiological importance of human placental Indoleamine 2,3-dioxygenase (EC 1.13.11.42), the first and rate-limiting enzyme in tryptophan metabolism, in regulating feto-maternal immunology has been studied. 2. Concentrations were measured in placental villous explant conditioned media of 14 amino acids that are known to be required for lymphocyte proliferation. In the absence of interferon-gamma only tryptophan and threonine were significantly lowered; in the presence of interferon-gamma (known to stimulate Indoleamine 2,3-dioxygenase) tryptophan but not threonine depletion was much greater. 3. Peripheral blood mononuclear cell proliferation determined by measuring thymidine incorporation into DNA following culture in the medium previously conditioned by culture of villous explants was markedly reduced when placental Indoleamine 2,3-dioxygenase was stimulated with interferon-gamma. Inhibition of placental Indoleamine 2,3-dioxygenase by 1-methyl-tryptophan prevented inhibition of thymidine incorporation. Supplementation of the conditioned medium with tryptophan but no other amino acid completely reversed the inhibition of thymidine incorporation. 4. Flow cytometric analysis showed that CD4-positive T lymphocyte division was specifically suppressed by Indoleamine 2,3-dioxygenase-mediated tryptophan depletion. This inhibition of T cell proliferation was due to arrest of cell cycle progression. 5. To study the mechanism of tryptophan sensing we examined the ability of 11 L-tryptophan analogues to support lymphocyte proliferation. Only L-tryptophan methyl and ethyl esters were able to stimulate proliferation in tryptophan-free media. Since both of these molecules are readily degraded to tryptophan by intracellular esterases this suggests that the tryptophan sensor is intracellular. 6. Our results show that mechanisms are present in the human placenta which are able to regulate cellular proliferation of the maternal immune system. This mechanism is dependent both on placental Indoleamine 2,3-dioxygenase-mediated tryptophan degradation and on tryptophan sensing systems within lymphocytes.

  • human placental Indoleamine 2 3 dioxygenase cellular localization and characterization of an enzyme preventing fetal rejection
    Biochimica et Biophysica Acta, 2000
    Co-Authors: Yoshiki Kudo, C A R Boyd
    Abstract:

    Abstract In order to test the hypothesis (Munn, Zhou, Attwood, Bondarev, Conway, Marshall, Brown, Mellor, Science 281 (1998) 1191–1193) that localized placental tryptophan catabolism prevents immune rejection of the mammalian fetus, the cellular localization and characteristics of human placental Indoleamine 2,3-dioxygenase (EC 1.13.11.42) were studied. The localization of Indoleamine 2,3-dioxygenase activity was determined quantitatively using cell fractionation by differential and discontinuous sucrose gradient centrifugation. Enzyme activity was looked for in isolated brush border microvillous plasma membranes of placental syncytiotrophoblast. We found that this membrane preparation (which showed a 32.4-fold purification from the starting homogenate with reference to the activity of a membrane marker enzyme, alkaline phosphatase (EC 3.1.3.1)) was strongly negatively enriched with Indoleamine 2,3-dioxygenase (which showed a one twenty-fifth decrease in its specific activity). Placental Indoleamine 2,3-dioxygenase is thus not expressed in the maternal facing brush border membrane of syncytiotrophoblast. 1-Methyl- dl -tryptophan which was used by Munn et al. as a key experimental tool for inhibiting Indoleamine 2,3-dioxygenase in the murine model showed a competitive inhibition of human placental Indoleamine 2,3-dioxygenase with l -tryptophan. The hypothesis, based on experiments performed in mouse, may therefore be applicable to avoidance of immune rejection of the fetus in human pregnancy.

C W G Redman - One of the best experts on this subject based on the ideXlab platform.

  • Indoleamine 2 3 dioxygenase distribution and function in the developing human placenta
    Journal of Reproductive Immunology, 2004
    Co-Authors: Osamu Takikawa, Yoshiki Kudo, C A R Boyd, Isabella Spyropoulou, C W G Redman, Takafumi Katsuki, Tetsuaki Hara, Koso Ohama, I L Sargent
    Abstract:

    Abstract Studies in mice have suggested that the placenta is protected from immune rejection by maternal T cells by means of localised Indoleamine 2,3-dioxygenase dependent depletion of tryptophan. To determine whether such mechanisms might operate in the human placenta, we have studied the physiological importance of human placental Indoleamine 2,3-dioxygenase immunohistochemically and functionally. Indoleamine 2,3-dioxygenase is detectable immunohistochemically from day 6 human blastocysts and thereafter throughout pregnancy in syncytiotrophoblasts, extravillous cytotrophoblasts and macrophages in the villous stroma and in the fetal membranes. Interferon-γ added to villous explants markedly stimulates Indoleamine 2,3-dioxygenase protein expression in macrophages. Indoleamine 2,3-dioxygenase-mediated tryptophan degradation in the first trimester villous and decidual tissue explants is stimulated by interferon-γ and inhibited by 1-methyl-tryptophan (an inhibitor of Indoleamine 2,3-dioxygenase). Peripheral blood mononuclear cell proliferation is controlled by Indoleamine 2,3-dioxygenase-mediated tryptophan degradation. These results suggest the cellular basis of a mechanism present at the human maternal–fetal interface involved in regulating the maternal immune response to conceptus.

  • decreased tryptophan catabolism by placental Indoleamine 2 3 dioxygenase in preeclampsia
    American Journal of Obstetrics and Gynecology, 2003
    Co-Authors: Yoshiki Kudo, C A R Boyd, I L Sargent, C W G Redman
    Abstract:

    Abstract Objective: Tryptophan degradation and depletion resulting from activation of Indoleamine 2,3-dioxygenase is characteristic of inflammatory reactions and may control their intensity. Normal third-trimester pregnancy is characterized by a maternal systemic inflammatory response, which is more intense in preeclampsia. Therefore, we studied tryptophan metabolism in pregnant women, with or without preeclampsia, as well as expression and function of placental Indoleamine 2,3-dioxygenase. Study Design: Plasma concentrations of tryptophan and kynurenine in women with preeclampsia, appropriately matched women with normal pregnancy, and healthy nonpregnant women were measured. Placental enzymatic activity and messenger RNA (mRNA) expression level of Indoleamine 2,3-dioxygenase were determined from the same placental material. Peripheral blood mononuclear cell proliferation was determined in medium conditioned by prior culture with villous tissue. Results: The plasma ratio of kynurenine to tryptophan, an in vivo index of enzyme activity, was significantly increased compared with nonpregnant controls in normal pregnancy but not in preeclampsia. The activity and mRNA expression level of Indoleamine 2,3-dioxygenase in term placentas were significantly lower in preeclampsia. Medium conditioned by culture of villous tissue explants of preeclampsia was less effective in inhibiting peripheral blood mononuclear cell proliferation compared with that of normal pregnancy. Conclusion: These observations suggest that in preeclampsia, reduced placental Indoleamine 2,3-dioxygenase activity (and relatively elevated plasma tryptophan) could cause dysregulation of the inflammatory response that is intrinsic to normal pregnancy. This may contribute to the pathogenesis of the maternal syndrome of preeclampsia. (Am J Obstet Gynecol 2003;188:719-26.)

  • tryptophan degradation by human placental Indoleamine 2 3 dioxygenase regulates lymphocyte proliferation
    The Journal of Physiology, 2001
    Co-Authors: Yoshiki Kudo, C A R Boyd, I L Sargent, C W G Redman
    Abstract:

    1. The physiological importance of human placental Indoleamine 2,3-dioxygenase (EC 1.13.11.42), the first and rate-limiting enzyme in tryptophan metabolism, in regulating feto-maternal immunology has been studied. 2. Concentrations were measured in placental villous explant conditioned media of 14 amino acids that are known to be required for lymphocyte proliferation. In the absence of interferon-gamma only tryptophan and threonine were significantly lowered; in the presence of interferon-gamma (known to stimulate Indoleamine 2,3-dioxygenase) tryptophan but not threonine depletion was much greater. 3. Peripheral blood mononuclear cell proliferation determined by measuring thymidine incorporation into DNA following culture in the medium previously conditioned by culture of villous explants was markedly reduced when placental Indoleamine 2,3-dioxygenase was stimulated with interferon-gamma. Inhibition of placental Indoleamine 2,3-dioxygenase by 1-methyl-tryptophan prevented inhibition of thymidine incorporation. Supplementation of the conditioned medium with tryptophan but no other amino acid completely reversed the inhibition of thymidine incorporation. 4. Flow cytometric analysis showed that CD4-positive T lymphocyte division was specifically suppressed by Indoleamine 2,3-dioxygenase-mediated tryptophan depletion. This inhibition of T cell proliferation was due to arrest of cell cycle progression. 5. To study the mechanism of tryptophan sensing we examined the ability of 11 L-tryptophan analogues to support lymphocyte proliferation. Only L-tryptophan methyl and ethyl esters were able to stimulate proliferation in tryptophan-free media. Since both of these molecules are readily degraded to tryptophan by intracellular esterases this suggests that the tryptophan sensor is intracellular. 6. Our results show that mechanisms are present in the human placenta which are able to regulate cellular proliferation of the maternal immune system. This mechanism is dependent both on placental Indoleamine 2,3-dioxygenase-mediated tryptophan degradation and on tryptophan sensing systems within lymphocytes.

I L Sargent - One of the best experts on this subject based on the ideXlab platform.

  • Indoleamine 2 3 dioxygenase distribution and function in the developing human placenta
    Journal of Reproductive Immunology, 2004
    Co-Authors: Osamu Takikawa, Yoshiki Kudo, C A R Boyd, Isabella Spyropoulou, C W G Redman, Takafumi Katsuki, Tetsuaki Hara, Koso Ohama, I L Sargent
    Abstract:

    Abstract Studies in mice have suggested that the placenta is protected from immune rejection by maternal T cells by means of localised Indoleamine 2,3-dioxygenase dependent depletion of tryptophan. To determine whether such mechanisms might operate in the human placenta, we have studied the physiological importance of human placental Indoleamine 2,3-dioxygenase immunohistochemically and functionally. Indoleamine 2,3-dioxygenase is detectable immunohistochemically from day 6 human blastocysts and thereafter throughout pregnancy in syncytiotrophoblasts, extravillous cytotrophoblasts and macrophages in the villous stroma and in the fetal membranes. Interferon-γ added to villous explants markedly stimulates Indoleamine 2,3-dioxygenase protein expression in macrophages. Indoleamine 2,3-dioxygenase-mediated tryptophan degradation in the first trimester villous and decidual tissue explants is stimulated by interferon-γ and inhibited by 1-methyl-tryptophan (an inhibitor of Indoleamine 2,3-dioxygenase). Peripheral blood mononuclear cell proliferation is controlled by Indoleamine 2,3-dioxygenase-mediated tryptophan degradation. These results suggest the cellular basis of a mechanism present at the human maternal–fetal interface involved in regulating the maternal immune response to conceptus.

  • decreased tryptophan catabolism by placental Indoleamine 2 3 dioxygenase in preeclampsia
    American Journal of Obstetrics and Gynecology, 2003
    Co-Authors: Yoshiki Kudo, C A R Boyd, I L Sargent, C W G Redman
    Abstract:

    Abstract Objective: Tryptophan degradation and depletion resulting from activation of Indoleamine 2,3-dioxygenase is characteristic of inflammatory reactions and may control their intensity. Normal third-trimester pregnancy is characterized by a maternal systemic inflammatory response, which is more intense in preeclampsia. Therefore, we studied tryptophan metabolism in pregnant women, with or without preeclampsia, as well as expression and function of placental Indoleamine 2,3-dioxygenase. Study Design: Plasma concentrations of tryptophan and kynurenine in women with preeclampsia, appropriately matched women with normal pregnancy, and healthy nonpregnant women were measured. Placental enzymatic activity and messenger RNA (mRNA) expression level of Indoleamine 2,3-dioxygenase were determined from the same placental material. Peripheral blood mononuclear cell proliferation was determined in medium conditioned by prior culture with villous tissue. Results: The plasma ratio of kynurenine to tryptophan, an in vivo index of enzyme activity, was significantly increased compared with nonpregnant controls in normal pregnancy but not in preeclampsia. The activity and mRNA expression level of Indoleamine 2,3-dioxygenase in term placentas were significantly lower in preeclampsia. Medium conditioned by culture of villous tissue explants of preeclampsia was less effective in inhibiting peripheral blood mononuclear cell proliferation compared with that of normal pregnancy. Conclusion: These observations suggest that in preeclampsia, reduced placental Indoleamine 2,3-dioxygenase activity (and relatively elevated plasma tryptophan) could cause dysregulation of the inflammatory response that is intrinsic to normal pregnancy. This may contribute to the pathogenesis of the maternal syndrome of preeclampsia. (Am J Obstet Gynecol 2003;188:719-26.)

  • tryptophan degradation by human placental Indoleamine 2 3 dioxygenase regulates lymphocyte proliferation
    The Journal of Physiology, 2001
    Co-Authors: Yoshiki Kudo, C A R Boyd, I L Sargent, C W G Redman
    Abstract:

    1. The physiological importance of human placental Indoleamine 2,3-dioxygenase (EC 1.13.11.42), the first and rate-limiting enzyme in tryptophan metabolism, in regulating feto-maternal immunology has been studied. 2. Concentrations were measured in placental villous explant conditioned media of 14 amino acids that are known to be required for lymphocyte proliferation. In the absence of interferon-gamma only tryptophan and threonine were significantly lowered; in the presence of interferon-gamma (known to stimulate Indoleamine 2,3-dioxygenase) tryptophan but not threonine depletion was much greater. 3. Peripheral blood mononuclear cell proliferation determined by measuring thymidine incorporation into DNA following culture in the medium previously conditioned by culture of villous explants was markedly reduced when placental Indoleamine 2,3-dioxygenase was stimulated with interferon-gamma. Inhibition of placental Indoleamine 2,3-dioxygenase by 1-methyl-tryptophan prevented inhibition of thymidine incorporation. Supplementation of the conditioned medium with tryptophan but no other amino acid completely reversed the inhibition of thymidine incorporation. 4. Flow cytometric analysis showed that CD4-positive T lymphocyte division was specifically suppressed by Indoleamine 2,3-dioxygenase-mediated tryptophan depletion. This inhibition of T cell proliferation was due to arrest of cell cycle progression. 5. To study the mechanism of tryptophan sensing we examined the ability of 11 L-tryptophan analogues to support lymphocyte proliferation. Only L-tryptophan methyl and ethyl esters were able to stimulate proliferation in tryptophan-free media. Since both of these molecules are readily degraded to tryptophan by intracellular esterases this suggests that the tryptophan sensor is intracellular. 6. Our results show that mechanisms are present in the human placenta which are able to regulate cellular proliferation of the maternal immune system. This mechanism is dependent both on placental Indoleamine 2,3-dioxygenase-mediated tryptophan degradation and on tryptophan sensing systems within lymphocytes.

Helen J. Ball - One of the best experts on this subject based on the ideXlab platform.

  • Indoleamine 2,3-dioxygenase 2 (IDO2) and the kynurenine pathway: characteristics and potential roles in health and disease
    Amino Acids, 2013
    Co-Authors: Amos A. Fatokun, Nicholas H. Hunt, Helen J. Ball
    Abstract:

    The kynurenine pathway is the major route for the oxidative degradation of the amino acid tryptophan. Activity of the pathway is involved in several disease conditions, both in the periphery and the central nervous system, including cancer, inflammatory disorders, neurological conditions, psychiatric disorders and neurodegenerative diseases. Three enzymes are now known to catalyze the first and rate-limiting step in the catabolism of tryptophan along this pathway: tryptophan 2,3-dioxygenase (TDO) and Indoleamine 2,3-dioxygenase (IDO, subsequently named IDO1), both of which have been extensively studied, and a third enzyme, Indoleamine 2,3-dioxygenase 2 (IDO2), a relative newcomer to the kynurenine pathway field. The adjuvant chemotherapeutic agent, 1-methyl-d-tryptophan, was intially suggested to target IDO2, implying involvement of IDO2 in tumorigenesis. Subsequently this compound has been suggested to have alternative actions and the physiological and pathophysiological roles of IDO2 are unclear. Targeted genetic interventions and selective inhibitors provide approaches for investigating the biology of IDO2. This review focuses on the current knowledge of IDO2 biology and discusses tools that will assist in further characterizing the enzymes of the kynurenine pathway.

  • Indoleamine 2 3 dioxygenase 2 a new enzyme in the kynurenine pathway
    The International Journal of Biochemistry & Cell Biology, 2009
    Co-Authors: Helen J. Ball, Hajime J Yuasa, Christopher J D Austin, Silvia Weiser, Nicholas H. Hunt
    Abstract:

    The kynurenine pathway of tryptophan metabolism converts the amino acid tryptophan into a number of biologically active metabolites. The first and rate-limiting step in this pathway is the conversion of tryptophan to N-formylkynurenine and until recently this reaction was thought to be performed by either of two enzymes, tryptophan 2,3-dioxygenase and Indoleamine 2,3-dioxygenase. A third enzyme, Indoleamine 2,3-dioxygenase-2, Indoleamine 2,3-dioxygenase-like protein or proto-Indoleamine 2,3-dioxygenase (IDO2, IDO-2, INDOL1 or proto-IDO), with this activity recently has been described. The gene encoding IDO2 is adjacent and structurally similar to the Indoleamine 2,3-dioxygenase gene and both mouse genes use multiple promoters to express transcripts with alternate 5' exons. The IDO2 protein is expressed in the murine kidney, liver, male and female reproductive system. The two IDO enzymes can utilise a similar range of substrates, however they differ in their selectivity for some inhibitors. The selective inhibition of IDO2 by 1-methyl-D-tryptophan suggests that IDO2 activity may have a role in the inhibition of immune responses to tumours.

  • Characterization and evolution of vertebrate Indoleamine 2, 3-dioxygenases. IDOs from monotremes and marsupials
    Comparative Biochemistry and Physiology B, 2009
    Co-Authors: Hajime J Yuasa, Helen J. Ball, Ghassan J Maghzal, Christopher J D Austin, Yuen Fern Ho, Camilla M. Whittington, Katherine Belov, Lars S. Jermiin, Nicholas H. Hunt
    Abstract:

    Abstract Indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO) are tryptophan-degrading enzymes that catalyze the first step in tryptophan catabolism via the kynurenine pathway. TDO is widely distributed in both eukaryotes and bacteria. In contrast, IDO has been found only in mammals and yeast. In 2007, a third enzyme, Indoleamine 2,3-dioxygenase-2 (IDO2), was discovered. IDO2 is found not only in mammals but also in lower vertebrates. Interestingly, the K m value of IDO2 for L-Trp was 500–1000 fold higher than that of IDO1. In this study, we isolated both IDO1 and IDO2 cDNA from a monotreme, the platypus ( Ornithorhynchus anatinus ), and a marsupial, the gray short-tailed opossum ( Monodelphis domestica ). We characterized the recombinant proteins and those of other known IDO1/IDO2 in intact cells and a cell-free system. It was found that methylene blue may not be suitable reductant for IDO2, hence resulting in an underestimation of recombinant IDO2 activity. In intact cells, the K m value of IDO2 for L-Trp was estimated to be much higher than that of IDO1 and this high K m value appears to have been conserved during the evolution of IDO2. The protein encoded by the ancestor gene of IDO1 and IDO2 is likely to have had properties more similar to present day IDO2 than to IDO1.

  • characterization of an Indoleamine 2 3 dioxygenase like protein found in humans and mice
    Gene, 2007
    Co-Authors: Helen J. Ball, Roland Stocker, Christopher J D Austin, Silvia Weiser, Lars S. Jermiin, Angeles Sanchezperez, Florian Astelbauer, James A Mcquillan, Nicholas H. Hunt
    Abstract:

    Indoleamine 2,3-dioxygenase (INDO) and tryptophan 2,3-dioxygenase (TDO) each catalyze the first step in the kynurenine pathway of tryptophan metabolism. We describe the discovery of another enzyme with this activity, Indoleamine 2,3-dioxygenase-like protein (INDOL1), which is closely related to INDO and is expressed in mice and humans. The corresponding genes have a similar genomic structure and are situated adjacent to each other on human and mouse chromosome 8. They are likely to have arisen by gene duplication before the origin of the tetrapods. The expression of INDOL1 is highest in the mouse kidney, followed by epididymis, and liver. Expression of mouse INDOL1 was further localized to the tubular cells in the kidney and the spermatozoa. INDOL1 was assigned its name because of its structural similarity to INDO. We demonstrate that INDOL1 catalyses the conversion of tryptophan to kynurenine therefore a more appropriate nomenclature for the enzymes might be INDO-1 and INDO-2, or the more commonly-used abbreviations, IDO-1 and IDO-2. Although the two proteins have similar enzymatic activities, their different expression patterns within tissues and during malaria infection, suggests a distinct role for each protein. This identification of INDOL1 may help to explain the regulation of the diversity of physiological and patho-physiological processes in which the kynurenine pathway is involved.